Transient focal cerebral ischemia is one of the most common types of ischemic stroke. Efforts to screen for agents/mechanisms that protect against cerebral ischemia/reperfusion (I/R) injury have not produced promising results. Interestingly, chronic heavy alcohol consumption increases the risk of ischemic stroke and produces neurodegeneration, whereas light alcohol consumption (LAC) decreases the risk of ischemic stroke and is neuroprotective. The present application will focus on identifying the cellular mechanisms of neuroprotection by LAC. Our aim is to translate these findings to humans suffering from the consequences of ischemic stroke. In our preliminary studies, we found that the neuroprotective effect of LAC appeared to be related to an increase in nuclear peroxisome proliferator-activated receptor gamma (PPAR?). We also found that LAC significantly attenuated transient focal cerebral ischemia-induced expression of inflammatory genes and DNA fragmentation. Further, lipocalin-type prostaglandin D2 synthase (L-PGDS) and manganese superoxide dismutase (MnSOD) were found to be upregulated in cerebral cortex by LAC. Based on these findings, our central hypothesis is that LAC protects against cerebral I/R injury by upregulating MnSOD via L-PGDS-mediated PPAR? activation. In specific aim #1, we propose to test the hypothesis that LAC attenuates vascular endothelial cell (VEC) inflammation and neuronal apoptosis following transient focal cerebral ischemia via an upregulated MnSOD. In specific aim #2, we propose to test the hypothesis that LAC attenuates VEC inflammation and neuronal apoptosis following transient focal cerebral ischemia via PPAR?-mediated MnSOD upregulation. In specific aim #3, we propose to test the hypothesis that LAC upregulates MnSOD and attenuates VEC inflammation and neuronal apoptosis following transient focal cerebral ischemia via L-PGDS-mediated PPAR? activation. The findings from these studies will have far-reaching implications, beyond that for LAC. We believe that by identifying the protective targets of LAC we will be able to apply therapy to manipulate these targets in individuals at risk for ischemic stroke.